Abstract Whole-genome amplification (WGA) technologies offer the opportunity to expand DNA from otherwise depleted native DNAs. This technique has the potential to facilitate the continued productivity of molecular epidemiological studies that have limited remaining DNA. Although allele amplification errors can occur, the performance of WGA in SNP genotyping has generally reported very good concordance and reproducibility. However the quality of WGA DNA obtained from buccal brushes has not been thoroughly evaluated for screening of mutations or sequencing, and published reports have mostly involved limited sets of DNA samples extracted from other sources and tested for the fidelity of non- PCR based WGA methods. The objective of this validation study is to determine the sensitivity and specificity of detecting germline mutations and polymorphisms in a large set of WGA DNA samples from a population-based study by direct sequencing. We plan to sequence the CDKN2A/p16 gene in 3580 DNA samples from buccal brushes that has been whole-genome amplified with the GenomePlex(R) kit, and then compare the sequencing data with those results already obtained in the original or native DNAs. We endeavor to demonstrate that we can use the WGA random fragmentation- PCR method to allow nearly unlimited future studies of germline DNA using this resource to investigate hypotheses in relation to melanoma risk and/or progression. The study also has a broader scientific relevance in that it will provide generalizable knowledge about the utility of buccal samples for future epidemiological investigations.